Intracellular pH links energy metabolism to lymphocyte death and proliferation

The role of intracellular pH (pHi) of lymphocytes in the control of the magnitude of immune response is unknown. We found that low pHi induces apoptosis of proliferating lymphocytes, whereas high pHi promotes their survival. In the ovalbumin sensitization and challenge model, energy metabolism is a major mechanism for regulating pHi. TCA cycle using carbohydrates lowers whereas glutaminolysis or aerobic glycolysis increases pHi. Proliferation powered by high mitochondrial membrane potentials (MMPs) in lymphocytes of low but not high pHi causes apoptosis. After antigenic challenge, lymphocytes of high pHi gradually increase and assume a positive relation between pHi and MMPs while lymphocytes of low pHi and an inverse relation between pHi and MMPs diminish. This change is at least partly dependent on glutaminolysis and aerobic glycolysis.